Abstract 16015: Human Cardiac Stem Cell Trafficking is Impaired with Age due to Alterations in Ephrin A1/EphA2 Signaling
Human cardiac stem cells (hCSCs) constitute a novel approach for the treatment of the failing heart. However, the age-associated decline in the pool of hCSCs with intact regenerative potential may negatively impact on the effectiveness of this therapy in the elderly. We report that senescent hCSCs are characterized by a marked decrease in the ability to translocate to sites of damage and initiate cardiomyogenesis. Thus, the objectives of our work were to identify the mechanisms controlling hCSC trafficking and develop strategies for the restoration of motility in old cells. We found that human myocytes express the ephrin A1 ligand and hCSCs possess the EphA2 receptor. Binding of ephrin A1 to EphA2 induced efficient mobilization of young hCSCs to the ischemic tissue promoting myocardial regeneration. We raised the possibility that abnormalities in ephrin/Eph signaling impair the migration of old hCSCs. In this regard, EphA2 knockdown in young hCSCs reduced their spontaneous motility and chemotaxis to levels similar to those observed in old cells. Although the EphA2 expression was comparable in young and senescent hCSCs, the activity of the receptor was inhibited in old cells as a result of post-translational oxidative modifications. In old hCSCs, ephrin A1-induced EphA2 autophosphorylation was significantly diminished. Consequently, activation of Src family kinases and phosphorylation of their substrate caveolin-1 were markedly attenuated. The insufficient binding of EphA2 to Src and caveolin-1 resulted in severe defects in the internalization of the ephrin A1. Fusion of the internalized receptor-ligand complex with the endocytic machinery was found to be required for actin cytoskeleton rearrangement and efficient cell movement. This process, which leads to the signaling endosome formation, was abrogated in senescent hCSCs. Importantly, overexpression of exogenous EphA2 receptor resistant to oxidative modifications reestablished the ephrin A1 signaling and the motility of old hCSCs in vitro and in vivo. Therefore, the ephrin A1/EphA2 axis may serve as a therapeutic target to reinstate the migratory capacity of old hCSCs and their ability to repair foci of injury, possibly restoring the structural and functional integrity of the senescent heart.
- © 2012 by American Heart Association, Inc.